COVID-19 and Thromboembolism: FAQs

What is the proposed pathophysiology of venous thromboembolism as a complication of COVID-19?

• COVID-19 triggers all three arms of Virchow’s triad: endothelial injury, hypercoagulability, and blood flow stasis.³
• COVID-19 may increase levels of von Willebrand factor and Factor VIII via endothelial injury.³
• Release of inflammatory cytokines (cytokine storm) could activate the coagulation cascade.² Antiphospholipid antibodies may play a role.² On autopsy, megakaryocytes have been found in unusually high numbers outside the bone marrow (e.g., in the lungs and heart).⁴
• Immobility, and treatments used for seriously ill COVID-19 patients such as fluid restriction and high PEEP, may cause blood flow stasis and microthrombi.³
• COVID-19-induced hypoxia facilities thrombus formation.¹
• Some drugs being investigated as treatments for COVID-19 may increase thrombosis risk directly (e.g., bevacizumab-induced CV events), or indirectly by reducing efficacy of antithrombotics (e.g., lopinavir/ritonavir may reduce clopidogrel conversion to its active metabolite).²
• Severely ill COVID-19 patients may have non-COVID-19-specific contributors to VTE risk, such as central lines.²
• DIC has been reported, but it is unclear if this is related to a specific effect of COVID-19, or a nonspecific complication of critical illness.² Contrary to what is usually seen in DIC, COVID-19 coagulopathy is characterized by normal or even increased fibrinogen.¹⁰ Moreover, overt bleeding seems not to be common in COVID-19 patients.^2,10

How does COVID-19-associated thromboembolism present clinically?

• In a German cohort of 12 autopsied patients (52 to 87 years of age) who died with a confirmed case of COVID-19, microthrombi were common in the lungs. Seven patients had DVT that had not been suspected before death. For four patients, PE was the cause of death.¹
• These findings suggest that clinicians should maintain a high index of suspicion for VTE in COVID-19 patients.¹
• Patients with severe COVID-19 may have myocardial injury (e.g., elevated troponin, electrocardiogram signs), which may be thrombotic ACS or myocarditis.²
• Hemostasis lab abnormalities seen in COVID-19 patients include elevated D-dimer, low platelets, prolonged PT, and shortened aPTT.²

For which COVID-19 patients should thromboembolism prophylaxis be considered, and how should it be provided?

• Experts advocate prophylaxis for all COVID-19 patients.^3,5,6 For patients with contraindications to anticoagulants such as active bleeding or platelets <25,000/mm³, use IPC.^2,3,5 Some experts feel it is reasonable to combine anticoagulants with IPC in critically ill COVID-19 patients, although benefit has not been demonstrated for non-COVID-19 patients.^3,11
• In general, use the same VTE prophylaxis regimens as for non-COVID patients.⁸ Consider LMWH for most patients, even those with DIC but without overt bleeding; it may decrease thrombin.² Fondaparinux is a choice for patients with heparin-induced thrombocytopenia.⁶ As for other acutely ill hospitalized patients, avoid prophylaxis with DOACs due to higher bleeding risk.³
• See our charts, Venous Thromboembolism Prophylaxis, Cancer-Associated Thrombosis FAQs, and LMWH Dosing in Special Populations (e.g., obesity) for prophylaxis options and dosing used in non-COVID patients. COVID-19 patients seem to have a higher risk of VTE than other critically ill patients, even with appropriate prophylaxis.¹² Therefore, some experts are using anticoagulant doses higher than those normally used for prophylaxis, such as twice-daily dosing of LMWH (e.g., enoxaparin 40 mg twice daily), or dosing as for VTE treatment, particularly in patients that seem to have higher thrombosis risk, such as those with D-dimer >6 x ULN, depending on bleeding risk, and stepping-down once the patient transfers out of intensive care.^6,8,9,11 If feasible, reserve higher doses for clinical trials⁶ (see www.clinicaltrials.gov). If, despite prophylactic anticoagulation, COVID-19 patients develop clots in vascular access devices or extracorporeal circuits, consider trying a different anticoagulant, or increasing the dose if bleeding risk allows.⁶
• Extrapolating from other populations, antiplatelets (e.g., aspirin) are likely inferior to anticoagulants for VTE prophylaxis in COVID-19 patients needing hospitalization.³
• Whether COVID-19 patients discharged from the hospital should continue thromboprophylaxis at home is unclear.⁶ Based on data from non-COVID medical patients, prophylactic anticoagulation could be considered for patients with low bleeding risk with VTE risks such as restricted mobility and active cancer, age ≥75 years, or D-dimer >2 ULN.^2,6,7 However, studies of extended-duration VTE prophylaxis in non-COVID medical patients don’t clearly show that VTE reduction outweighs bleeding risk.⁷ Consider extended prophylaxis for patients similar to those in clinical trials of extended VTE prophylaxis in medical patients, using an agent (rivaroxaban, betrixaban), dose, and duration used in clinical trials.¹¹ Ensure that the dose, purpose, and duration of VTE prophylaxis is clearly communicated to the outpatient prescriber.¹¹
• For patients with mild COVID-19 who are isolating at home, advise keeping active.² Pharmacologic prophylaxis may be considered for very high-risk patients (e.g., immobility, history of VTE, active cancer) without high bleeding risk.²

How is thromboembolism in COVID-19 patients treated?

• Anticoagulation, for at least three months, is the mainstay of treatment.^{2,3 Initiate} treatment with a parenteral agent in critically ill patients.³
• For patients with recurrent VTE despite appropriate anticoagulation, consider switching from oral therapy to LMWH, or increasing the LMWH dose by 25% to 30% in patients failing standard-dose LMWH, based on low-quality evidence in other populations.³
• Catheter-directed therapy or systemic thrombolysis should be reserved for the most serious cases.^2.3 See our chart, Pulmonary Embolism: Focus on Thrombolytics, for more information.
• Reserve IVC filters for recurrent PE despite appropriate anticoagulation, or clinically important VTE with absolute contraindications to anticoagulation.²

What are some general considerations for antithrombotic use of special relevance to COVID-19?

• For patients who might need procedures, consider parenteral antithrombotics over oral antithrombotics due to shorter duration of action.²
• DOACs may be difficult to manage in this patient population due to clinical instability resulting in impaired oral drug absorption or deterioration of renal function, and drug interactions with COVID-19 treatments.³
• In the hospital, consider fondaparinux (not for intensive care patients) or LMWH over UFH to reduce caregiver viral exposure and to reduce the risk of missed doses; fondaparinux and LMWH require less frequent blood draws for monitoring and fewer daily doses.^2,3 However, UFH might be preferred for patients with hemodynamic instability or renal insufficiency due to quicker offset.³
• In patients with ACS and elevated bleeding risk (e.g., due to DIC), consider clopidogrel over other antiplatelets.²
• In patients taking antithrombotics chronically who develop known or suspected DIC without overt bleeding, consider risk/benefit of reducing the intensity of therapy or discontinuation. For example, in patients taking DAPT, consider risk/benefit of continuing DAPT if platelets ≥50,000/mm³, switching to a single antiplatelet if platelets are ≥25,000 to <50,000/mm³, or discontinuing if platelets <25,000/mm³.²
• In outpatients, consider a DOAC or LMWH over warfarin if home or drive-in INR monitoring is not available, assuming use is feasible given cost, indication (e.g., prosthetic heart valve), comorbidities (e.g., pregnancy), etc.^2,8
• Outpatients with COVID-19 and previously diagnosed thrombotic or CV disease should generally continue their usual antithrombotic regimen (e.g., aspirin, anticoagulant).² But for patients taking warfarin, consider transitioning to a DOAC or LMWH.²
• Educate outpatients taking antithrombotics to discern clinically important bleeding from nuisance bleeding to reduce unnecessary emergency room visits.²
• Be alert for drug interactions between antithrombotics and drugs used to treat COVID-19. Select drug interactions are covered in the next section. Consider using injectable antithrombotics when drug interactions are a concern.²

What are some select drug interactions between antithrombotics and drugs being investigated to treat COVID-19?

• Warfarin: Monitor INR and adjust dose as appropriate (e.g., with methylprednisolone, azithromycin, lopinavir/ritonavir, interferon, ribavirin, sarilumab, tocilizumab)^2,6
• DOACs:
• Apixaban: reduce apixaban dose by 50% with lopinavir/ritonavir (avoid if initial apixaban dose is 2.5 mg twice daily).²
• Rivaroxaban: avoid with lopinavir/ritonavir.²
• Edoxaban: avoid with lopinavir/ritonavir. Limit edoxaban dose to 30 mg once daily for VTE treatment with azithromycin.²
• Betrixaban: reduce dose to 80 mg x 1, then 40 mg once daily with lopinavir/ritonavir or azithromycin.²
• Dexamethasone is a CYP3A4 inducer, but whether it significantly reduces DOAC efficacy is unknown.⁶
• Antiplatelets:²
• Clopidogrel: lopinavir/ritonavir may decrease efficacy via CYP3A4 inhibition of formation of active metabolite. Switch to prasugrel with caution, or use P2Y12 platelet function assay to monitor efficacy.
• Ticagrelor: lopinavir/ritonavir may increase effects via CYP3A4 inhibition. Consider prasugrel (with caution), reduce dose (not commonly done), or use P2Y12 platelet function assay to monitor effect.
• Cilostazol (U.S.): lopinavir/ritonavir may increase effect via CYP3A4 inhibition. Limit dose to 50 mg twice daily.
• See www.covid19-druginteractions.org for more interactions.